Expanding the landscape of immunotherapy targets

Most searches for druggable tumor-specific antigens (TSAs) start with an examination of peptides derived from protein-coding exons. Laumont et al. took a different approach and found numerous TSAs aberrantly expressed from noncoding sequences in murine cell lines and in B-lineage acute lymphoblastic leukemia and lung cancer patient samples, but not in cells responsible for T cell selection. The authors validated the immunogenicity and efficacy of TSA vaccination for select antigens in mouse models of cancer. The finding that noncoding regions are a potentially rich source of TSAs could greatly expand the number of targetable antigens across different cancers, including those with low mutational burdens.

Abstract

Tumor-specific antigens (TSAs) represent ideal targets for cancer immunotherapy, but few have been identified thus far. We therefore developed a proteogenomic approach to enable the high-throughput discovery of TSAs coded by potentially all genomic regions. In two murine cancer cell lines and seven human primary tumors, we identified a total of 40 TSAs, about 90% of which derived from allegedly noncoding regions and would have been missed by standard exome-based approaches. Moreover, most of these TSAs derived from nonmutated yet aberrantly expressed transcripts (such as endogenous retroelements) that could be shared by multiple tumor types. Last, we demonstrated that, in mice, the strength of antitumor responses after TSA vaccination was influenced by two parameters that can be estimated in humans and could serve for TSA prioritization in clinical studies: TSA expression and the frequency of TSA-responsive T cells in the preimmune repertoire. In conclusion, the strategy reported herein could considerably facilitate the identification and prioritization of actionable human TSAs.